Substituted azafused ring compounds and medical uses thereof

Abstract

The present application relates to a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, and compositions, combination compositions and uses thereof. The compound is effective to inhibit ATR kinase activity and is useful for treating ATR kinase-mediated hyperproliferative diseases in a patient.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical technology, specifically to a substituted nitrogen-containing fused ring compound and its pharmaceutical uses, and more specifically to a compound with the structure shown in Formula I, or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof, and methods for its preparation, compositions thereof, combination drug compositions thereof, and their applications. Background Technology

[0002] The integrity of the eukaryotic genome is protected by a complex signaling pathway called DNA damage response (DDR) and multiple DNA repair mechanisms. When DNA is damaged in the body, activation of the DDR pathway leads to cell cycle arrest, inhibition of overall translation, induction of DNA repair, and ultimately, cell survival or cell death. Proteins that can directly recognize abnormal DNA structures include ATM (ataxia-telangiectasia mutation), ATR (ATM- and Rad3-associated UniProtKB / Swiss-ProtQ13535), and DNA-PKcs (DNA-dependent protein kinases).

[0003] ATR belongs to the phosphatidylinositol-3-kinase-like kinase (PIKK) family and is a major member of the DNA damage checkpoint (Cimprich KA and Cortez D. 2008, Nature Rev. Mol. Cell Biol. 9: 616-627). Once activated by exogenous or endogenous DNA damage and replication problems (such as replication fork stress, DNA double-strand breaks, and alkylating agents), ATR regulates cell cycle progression, replication fork stability, and DNA repair by phosphorylating various substrates (Chk1, WRN, Marcal1, and FANCI, etc.), thereby promoting the survival of cells under replication stress and with DNA damage (Clin Cancer Res, 2015, Nov 1; 21(21): 4780-4785). The ATR signaling pathway is crucial for tumor cells with abnormal oncogenic proteins. Many cancer cells lack key tumor suppressor genes, which makes them more dependent on the ATR pathway to regulate cellular DNA damage repair and promote cell survival than normal cells. Therefore, ATR has become a promising target for cancer therapy. Preclinical in vitro or in vivo studies have shown that ATR inhibitors are more effective in tumor cells than in normal cells, and that ATR inhibition has a synthetic lethal effect on various tumorigenesis events (such as Ras overexpression and ATM deficiency).

[0004] ATR inhibitors can be used alone or in combination with DNA-damaging agents for cancer treatment because they disrupt DNA replication mechanisms, which are more crucial for cell survival in many cancer cells than in healthy cells. In fact, ATR inhibitors have been proven effective as single-active agents in cancer cells and can serve as effective sensitizers for radiotherapy and chemotherapy. Furthermore, ATR inhibitors can be used in combination with other DDR-related targeted therapies, such as PARP inhibitors. Summary of the Invention

[0005] This invention aims to at least partially address the technical problems existing in the prior art. To this end, this invention proposes a compound of Formula I, or its stereoisomers, tautomers, salts, mixtures thereof, or combinations thereof, uses, and pharmaceutical combinations thereof, which can effectively inhibit ATR kinase activity and can be used to treat ATR kinase-mediated hyperproliferative diseases in patients, showing broad prospects for drug development.

[0006] In one aspect of the invention, a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof, or a salt thereof, or a mixture thereof is provided:

[0007]

[0008] Among them, X1, X2 and X3 are each independently N or CH, and X1, X2 and X3 are not simultaneously N or CH;

[0009] When X2 is N and X3 is CH, X3 can be arbitrarily further divided by R. 3 Replace; R 1 It is a 5- to 7-membered heteroaryl group containing 1-3 N atoms; R 2 Hydrogen, halogen, -NR 4 R 5 CN, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered heterocyclic C0-C3 alkyloxy, C2-C6 alkenyl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclic C0-C3 alkyl, 4- to 10-membered heterocyclic C2-C3 alkenyl, phenyl, 4- to 10-membered heteroaryl, -(CO)OR 4 -(CO)NR 4 R 5 -(SO2)R 6 -(SO)R 6 -SR 6 -(SO2)NR 4 R 5 -NR 4 (SO2)R 6 -((SO)=NR 8 )R 7-CR 6 R 7 (SO2)R n -CR 6 R 7 ((SO)=NR 8 )R n -N=(SO)R 6 R 7 -(PO)(OR) 4 )2、-(PO)(OR 4 )R 7 or -(PO)(R 7 )2; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered heterocyclic C0-C3 alkyloxy, C2-C6 alkenyl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclic C0-C3 alkyl, 4- to 10-membered heterocyclic C2-C3 alkenyl, phenyl, or 4- to 10-membered heteroaryl is optionally substituted by at least one of the following groups: halogen, -OH, -NR 4 R 5 C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic C0-C3 alkyl, phenyl, -(CO)OR 4 -(CO)NR 4 R 5 -NR 4 (CO)R 7 -NR 5 (CO)OR 4 -NR 5 (CO)NR 4 R 5 -(SO2)R 6 -(SO)R 6 -SR 6 -(SO2)NR 4 R 5 -NR 4 (SO2)R 6 -((SO)=NR 8 )R 7 -CR 6 R 7 (SO2)R n -CR 6 R 7 ((SO)=NR 8 )R n -N=(SO)R 6 R 7 -(PO)(OR) 4 )2、-(PO)(OR 4 )R 7、-(PO)(R 7 2. Furanyl or pyrazolyl, wherein the C1-C6 alkyl group is optionally converted by one or more halogens, -OH, phenyl, -(CO)OR 4 C3-C6 cycloalkyl, 3- to 10-membered heterocyclic C0-C3 alkoxy substitution; R 3 It is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy or halogen;

[0010] R 4 and R 5 Each is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl, wherein the phenyl is optionally substituted with one or more halogens; or, R 4 and R 5 Together with the attached atom, it forms a 4, 5, 6 or 7-membered cyclic amine group, which is optionally substituted by one or more C1-C6 alkyl or C1-C6 haloalkyl groups, and the 4, 5, 6 or 7-membered cyclic amine group optionally contains an additional heteroatom selected from O, N and S.

[0011] R 6 It is hydrogen, C1-C4 alkyl or phenyl, wherein the C1-C4 alkyl or phenyl is optionally converted by one or more R 9 replace;

[0012] R 7 It is hydrogen, C1-C4 alkyl; or, in CR 6 R 7 (SO2)R n CR 6 R 7 ((SO)=NR 8 )R n and -N=(SO)R 6 R 7 In the case of groups, R 6 and R 7 Together with the attached atoms, they form C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl;

[0013] R 8 It is hydrogen, C1-C4 alkyl, -(CO)OR 4 -(CO)NR 4 R 5 Or CN;

[0014] R 9 Halogen, OH, -NR 4 R 5CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl, -(CO)OR 4 or (CO)NR 4 R 5 ;R n It is a C1-C4 alkyl or a C3-C7 cycloalkyl.

[0015] Through extensive experiments, the inventors discovered that this compound can effectively inhibit ATR kinase activity, especially exhibiting excellent inhibitory activity against tumor cells. It can be used to treat ATR kinase-mediated hyperproliferative diseases in patients and has broad prospects for drug development.

[0016] According to embodiments of the present invention, the above-described compound, or its stereoisomer, or its tautomer, or its salt, or mixture thereof, may further comprise at least one of the following additional technical features:

[0017] According to embodiments of the present invention, the compound, or its stereoisomer, its tautomer, its salt, or a mixture thereof, has a structure represented by formula (Ia), (Ib), or (Ic):

[0018]

[0019] According to an embodiment of the present invention, R 1 Selected from at least one of the following groups:

[0020]

[0021] According to an embodiment of the present invention, R 1 for

[0022] According to an embodiment of the present invention, R 1 for

[0023] According to an embodiment of the present invention, R 2 It is a C1-C3 alkyl, C1-C3 alkoxy, 4- to 6-membered heterocyclic C1-C3 alkoxy, 4- to 6-membered heteroaryl, -CR 6 R 7 (SO2)R n or -CR 6 R 7 ((SO)=NR 8 )R n ;

[0024] Wherein, the C1-C3 alkoxy, 4- to 6-membered heterocyclic C1-C3 alkoxy, or 4- to 6-membered heteroaryl group is optionally substituted with at least one of the following groups:

[0025] -(CO)OR 4 C3-C6 cycloalkyl, C1-C3 alkyl, or 3- to 6-membered heterocyclic C1-C3 alkyl, wherein the C1-C3 alkyl is optionally converted by one or more halogens, -OH, -(CO)OR 4 C3-C6 cycloalkyl, 3- to 5-membered heterocyclic C0-C3 alkoxy substitution;

[0026] R 4 It is hydrogen or C1-C2 alkyl;

[0027] R 6 and R 7 Each is independently hydrogen, C1-C2 alkyl; or, R 6 and R 7 Together with the attached atoms, they form C3-C7 cycloalkyl groups;

[0028] R 8 It is hydrogen or C1-C2 alkyl;

[0029] R n It is a C1-C2 alkyl or a C3-C7 cycloalkyl.

[0030] According to embodiments of the present invention, the 4 to 10 heteroaryl groups are pyrroloyl, pyrazolyl, thiophenolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-b]pyridyl, oxadiazolyl, indolyl, benzothiophenolyl, quinolinyl, or isoquinolinyl.

[0031] According to an embodiment of the present invention, R 2 Selected from at least one of the following groups:

[0032]

[0033] According to an embodiment of the present invention, R 2 Selected from one of the following groups:

[0034]

[0035] According to embodiments of the present invention, the compound, or its stereoisomer, or its tautomer, or its salt, or a mixture thereof, comprises at least one of the following structures:

[0036]

[0037]

[0038]

[0039]

[0040] In another aspect, the present invention also provides a composition. According to embodiments of the present invention, the composition comprises the above-described compound, or its stereoisomers, tautomers, salts, or mixtures thereof. The composition prepared using the aforementioned compound, or its stereoisomers, tautomers, salts, or mixtures thereof, can effectively inhibit ATR kinase activity, especially exhibiting good inhibitory activity against tumor cells, and can be used to treat ATR kinase-mediated hyperproliferative diseases in patients, showing broad prospects for drug development.

[0041] According to embodiments of the present invention, the composition may further include other formulations, wherein the two individual formulations may be applied simultaneously or sequentially.

[0042] According to embodiments of the present invention, the composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

[0043] In another aspect, the present invention also provides the use of the above-described compound, or its stereoisomer, or its tautomer, or its salt, or a mixture thereof, or the above-described composition, in the preparation of a medicament for the prevention or treatment of hyperproliferative diseases. The medicament of the present invention can effectively inhibit ATR kinase activity and can be used to treat hyperproliferative diseases in patients.

[0044] According to embodiments of the present invention, the hyperproliferative diseases include psoriasis, keloids and other skin hyperplasia, benign prostatic hyperplasia, and tumors.

[0045] According to embodiments of the present invention, the tumors include melanoma, brain tumors, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumors, bladder cancer, or gallbladder cancer.

[0046] In another aspect, the present invention also provides a combination drug composition. According to embodiments of the present invention, the combination drug composition is used for the prevention or treatment of hyperproliferative diseases, comprising the above-described compound, or its stereoisomers, tautomers, salts, mixtures thereof, or combinations thereof; and other drugs for the prevention or treatment of hyperproliferative diseases. The combination drug composition of the present invention can effectively inhibit ATR kinase activity and can be used to treat hyperproliferative diseases in patients.

[0047] According to embodiments of the present invention, the "combined drug composition" may be a single compound preparation or a composition of two or more individual preparations, wherein the two individual preparations may be administered simultaneously or sequentially, and the effect of using the two or more individual preparations is significantly greater than the effect of using one or some of the individual preparations alone.

[0048] According to embodiments of the present invention, the other drugs for preventing or treating proliferative diseases include at least one of the following anticancer drugs: cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, mitoxantrone, methyl hydroxyrosine, mentholtoporp, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, and oxaliplatin. Narcissus, Vincristine, Vincristine, Vinorelbine, Paclitaxel, Ixapiron, Cabazitaxel, Docetaxel, Monoclonal Antibody, Panitumumab, Nezotuzumab, Nivolumab, Pembrolizumab, Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obintoluizumab, Ofatumumab, Rituximab, Alemumab, Teimozumab, Tosimo, Bentoximab, Daremumab, Erotoluizumab, Ofatumumab, Dinut uximab), belintolimab (Blinatumomab), Avastin, Herceptin, Rituxan, imatinib, gefitinib, erlotinib, ostinib, afatinib, celitinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, tebuconazole, everolimus, vorinostat, romidesin, pabistat, belitistat, tamoxifen, letrozole, fulvestrant, mitoxantridine, octreotide, retinoic acid, tretinoin cream, Zoledronic acid, bortezomib, carfilzomib, ixazomib, sonidazole, denosumab, thalidomide, lenalidomide, pomalidomide, venetoclax, recombinant human interleukin-2 (Aldesleukin), Sipueucel-T (prostate cancer treatment vaccine), palbociclib, olaparib, niraparib, rucaparib, and talazoparib.

[0049] In another aspect, the present invention also provides the use of the aforementioned combination drug composition in the preparation of a medicament for the prevention or treatment of hyperproliferative diseases.

[0050] In another aspect, the present invention also provides a method for preventing or treating hyperproliferative disorders. According to embodiments of the invention, the method includes administering to a subject a pharmaceutically acceptable amount of the aforementioned compound, the aforementioned composition, or a combination of the aforementioned drugs. Using the method of the present invention, the activity of ATR kinase in the subject can be inhibited, effectively treating the patient's hyperproliferative disorder.

[0051] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0052] In the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0053] In this article, the terms “halogen atom,” “halo-”, or “halo-” refer to fluorine, chlorine, bromine, or iodine atoms.

[0054] In this article, the term "C1-C" n "Alkyl" refers to a saturated monovalent hydrocarbon group with a straight chain or branched chain having 1, 2, 3, 4, 5, ..., or n carbon atoms. The term "C1-C6 alkyl" refers to a saturated monovalent hydrocarbon group with a straight chain or branched chain having 1, 2, 3, 4, 5, or 6 carbon atoms, such as: methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, ... 2-Ethylbutyl, 1-Ethylbutyl, 3,3-Dimethylbutyl, 2,2-Dimethylbutyl, 1,1-Dimethylbutyl, 2,3-Dimethylbutyl, 1,3-Dimethylbutyl, and 1,2-Dimethylbutyl, or isomers of the above groups. In particular, the groups may have 1, 2, 3, or 4 carbon atoms (“C1-C4 alkyl”), for example: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, and tert-butyl; more particularly, the groups may have 1, 2, or 3 carbon atoms (“C1-C3 alkyl”), for example: methyl, ethyl, n-propyl, or isopropyl.

[0055] In this document, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by the same or different halogen atoms, i.e., one halogen atom is independent of another halogen atom, wherein "C1-C6 alkyl" is as defined above. In particular, the halogen atom is F, for example: the C1-C6 haloalkyl group may be -CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3.

[0056] In this document, the term "C1-C4 hydroxyalkyl" refers to a C1-C4 alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups, as defined above. Examples include: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, and 1-hydroxy-2-methyl-propyl.

[0057] In this document, the terms "C1-C6 alkoxy" and "C1-C6 alkyloxy" refer to C1-C6 alkyl groups containing the formula "-O-alkyl", wherein the term "alkyl" is as defined above. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy, and n-hexyloxy, or isomers of the above groups. In particular, the "C1-C6 alkoxy" may contain 1, 2, 3, 4, or 5 carbon atoms ("C1-C5 alkoxy"), preferably, it may contain 1, 2, 3, or 4 carbon atoms ("C1-C4 alkoxy").

[0058] In this document, the term "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy group in which one or more hydrogen atoms are replaced by the same or different halogen atoms, as defined above. In particular, the halogen atom is F, for example: the C1-C6 haloalkoxy group may be -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.

[0059] In this document, the term "C2-C6 alkenyl" refers to a C2-C6 alkoxy group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, or 2, 3, or 4 carbon atoms ("C2-C4 alkenyl"), especially 2 or 3 carbon atoms ("C2-C3 alkenyl"). It should be understood that when the alkenyl group contains more than one double bond, the double bonds can be separable or conjugated with each other. Examples include: vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2 -alkenyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, Isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-Dimethylprop-2-enyl, 1-Ethylprop-1-enyl, 1-Propylvinyl, 1-Isopropylvinyl, 4-Methylpent-4-enyl, 3-Methylpent-4-enyl, 2-Methylpent-4-enyl, 1-Methylpent-4-enyl, 4-Methylpent-3-enyl, (E)-3-Methylpent-3-enyl, (Z)-3-Methylpent-3-enyl, (E)-2-Methylpent-3-enyl, (Z)-2-Methylpent-3-enyl, (E)-1-Methylpent-3-enyl, (Z)-1-Methylpent-3-enyl, (E)-4-Methylpent-2-enyl, (Z)-4-Methylpent-2-enyl, (E)- 3-Methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethyl 3-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl -2-alkenyl, (E)-2-propylprop-1-alkenyl, (Z)-2-propylprop-1-alkenyl, (E)-1-propylprop-1-alkenyl, (Z)-1-propylprop-1-alkenyl, (E)-2-isopropylprop-1-alkenyl, (Z)-2-isopropylprop-1-alkenyl, (E)-1-isopropylprop-1-alkenyl, (Z)-1-isopropylprop-1-alkenyl, (E)-3,3-dimethylprop-1-alkenyl, (Z)-3,3-dimethylprop-1-alkenyl, 1-(1,1-dimethylethyl)vinyl, but-1,3-dienyl, pent-1,4-dienyl, hex-1,5-dienyl, or methylhexadienyl. Especially vinyl or allyl.

[0060] In this document, the term "C3-C7 cycloalkyl" or "3- to 7-membered cycloalkyl" refers to a saturated monovalent mono- or bicyclic hydrocarbon ring containing 3, 4, 5, 6, or more carbon atoms. The C3-C7 cycloalkyl is a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; the C3-C... 10 The cycloalkyl group is a bicyclic hydrocarbon ring, such as perhydrocyclopentadiene or decahydronaphthalene ring. In particular, the ring contains 3, 4, 5 or 6 carbon atoms (“C3-C6 cycloalkyl”), preferably cyclopropyl.

[0061] In this document, the term "3- to 10-membered heterocyclic CO-C3 alkyl" refers to a CO-C3 alkyl group in which the alkyl group is replaced by a 3- to 10-membered heterocyclic group, i.e., -(CO-C3 alkyl)-R, where R is a 3- to 10-membered heterocyclic group. The 3- to 10-membered heterocyclic CO-C3 alkyl group can be monocyclic, but is not limited thereto. For example, it can be a 4-membered ring (e.g., azirrobutyl, oxobutyl), or a 5-membered ring (e.g., tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrololinyl), or a 6-membered ring (e.g., tetrahydropyranyl, piperidinyl, morpholinyl, dithiohexyl, thiomorpholinyl, piperazinyl, or trithiaalkyl), or a 7-membered ring (e.g., diazaheptanyl ring). Optionally, the heterocyclic alkyl group can be benzofused. Tetrahydrofuranyl, tetrahydropyranyl, or piperazinyl are preferred.

[0062] The 3 to 10-membered heterocyclic C0-C3 alkyl group can be bicyclic, but is not limited thereto. For example, it can be a 5,5-membered ring (e.g., hexahydrocyclopentadien[c]pyrrolo-2(1H)-yl ring) or a 5,6-membered bicyclic ring (e.g., hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring).

[0063] As described above, for example, the nitrogen-containing ring may be partially unsaturated, that is, it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl ring; for example, benzofused; for example, but not limited to, dihydroisoquinoline ring.

[0064] In this document, the term “3 to 10-membered heterocyclic CO-C3 alkyloxy” means that the alkyl group in CO-C3 alkyloxy is replaced by a 3 to 10-membered heterocyclic group, i.e., -O-(CO-C3 alkyl)-R, where R is a 3 to 10-membered heterocyclic group, such as pyrrolidineoxy, tetrahydrofuranoxy, or tetrahydropyranoxy.

[0065] In this paper, the term "3 to 10-membered heterocyclic C0-C3 alkyl" refers to C0-C3 alkyl groups substituted with 3 to 10-membered heterocyclic groups.

[0066] In this paper, the term "4 to 10-membered heterocyclic C2-C3 alkenyl" refers to the substitution of C2-C3 alkenyl groups with 4 to 10-membered heterocyclic groups.

[0067] In this article, the terms "alkyloxy" and "alkoxy" are used synonymously.

[0068] It should be noted that, in this document, generally and unless otherwise stated, heteroaryl or hypoaryl includes all its possible isomers, such as its positional isomers. Thus, for some illustrative and non-limiting examples, the term "pyridyl" or "pyridylene" includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; or the term thiophenyl or thiopheneyl includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl.

[0069] In this paper, the terms "-OR", "-NRR", etc. refer to R groups being connected to oxygen or nitrogen atoms by a single bond.

[0070] In this article, the oxygen atom in the terms "-C(O)R", "-S(O)2R", etc., is connected to a carbon or sulfur atom by a double bond.

[0071] It should be noted that the term "C1-C6" as used herein, for example, in the context of the definitions of "C1-C6 alkyl," "C1-C6 haloalkyl," "C1-C6 alkoxy," or "C1-C6 haloalkoxy," refers to an alkyl group having a finite number of carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Further understanding, the term "C1-C6" should be interpreted as including any subrange such as C1-C6, C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5; especially C1-C2, C1-C3, C1-C4, C1-C5, C1-C6; more especially C1-C4; and in the case of "C1-C6-haloalkyl" or "C1-C6-haloalkoxy," even more especially C1-C2.

[0072] Similarly, as used herein, the term “C2-C6” throughout its usage, for example, in the context of the definitions of “C2-C6 alkenyl” and “C2-C6 alkynyl”, should be understood to refer to an alkenyl or alkynyl group having a finite number of carbon atoms, i.e., 2, 3, 4, 5, or 6 carbon atoms. Further understood, the term “C2-C6” should be interpreted to include any subranges thereof, such as C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C3; especially C2-C3.

[0073] Furthermore, the term "C3-C6" as used herein, for example, in the context of the definition of "C3-C6 cycloalkyl", should be understood to refer to a cycloalkyl group having a finite number of carbon atoms, i.e., 3, 4, 5, or 6 carbon atoms. Further understanding, the term "C3-C6" should be interpreted as any sub-regions included therein, such as C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C6; especially C3-C6.

[0074] Furthermore, as used herein, the term “C2-C4” throughout its usage, for example in the context of the definition of “C2-C4-alkenyl,” should be understood to refer to an alkenyl group having a finite number of carbon atoms, i.e., 2, 3, or 4 carbon atoms. Further understood, the term “C2-C4” should be interpreted as any sub-regions included therein, such as C2-C4, C2-C3, and C3-C4.

[0075] In the description of the functional groups of this invention It is used to describe the position of the substituent group.

[0076] In this document, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specified atom by a group selected from those indicated, provided that the substitution does not exceed the normal valence of the specified atom under its existing condition, and that the substitution produces a stable compound. Substituents and / or variables may be combined, as long as such combinations produce a stable compound.

[0077] In this article, the terms "stable compound" or "stable structure" refer to a sufficiently robust compound that can withstand separation from the reaction mixture to effective purity and can be formulated into an effective therapeutic agent.

[0078] In this document, the terms "optionally substituted" or "optionally replaced" refer to optional substitution by a specific group, radical, or part thereof. Ring system substitution refers to a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces a available hydrogen atom in the ring system.

[0079] It should be noted that "multiple groups are optionally replaced by multiple substituents" can mean that the same group can be replaced by the same substituent multiple times, or that each group can be replaced by different substituents.

[0080] In this document, the term “can be further replaced” means that “replacement” may but does not have to happen, including situations where it may or may not occur.

[0081] In this document, the term "one or more" (e.g., in the definition of substituents in compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, and even more especially one or two".

[0082] It should be noted that the compounds of the present invention also include all suitable isotopic variants of the compounds of the present invention. An isotopic variant of the compounds of the present invention is defined as a compound of the present invention in which at least one atom is replaced by an atom of the same atomic number but with an atomic weight different from that of atoms commonly or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include the following isotopes: hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example: 2 H (deuterium) 3 H (tritium) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 129 I and 131 I. Certain isotopic variants of the compounds of the present invention, for example, the introduction of one or more radioactive isotopes (e.g.: 3 H or 14 Variants of C) are used for drug and / or substrate tissue partitioning studies. Tritium and carbon-14 are particularly preferred. 14 C) Isotopes, because they are easy to prepare and detect.

[0083] Furthermore, substitution with an isotope (e.g., deuterium) can provide certain therapeutic advantages due to greater metabolic stability, such as an increased half-life in vivo or a reduced dosage requirement, and is therefore preferred in some cases. Isotopic variants of the compounds of the present invention can typically be prepared using conventional methods known to those skilled in the art, for example, using suitable isotopic variants with suitable reagents, employing illustrative methods or preparation examples described in the examples below.

[0084] It should be noted that, depending on the position and nature of the various substituents of interest, the compounds of the present invention may contain one or more asymmetric centers. The asymmetric carbon atom may exist in (R) or (S) configurations, forming a racemic mixture in the case of a single asymmetric center, and a diastereomeric mixture in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to the racking effect around a given bond, for example, the central bond connecting the two substituted aromatic rings of a particular compound.

[0085] It should be noted that the compounds of the present invention may also contain asymmetric sulfur atoms, such as asymmetric sulfoxide or sulfoxide imine groups with the following structures:

[0086]

[0087] In this context, * indicates an atom that can bond with the rest of the molecule. Substituents on the ring can also be present in cis or trans configurations. This means that all such configurations (including enantiomers and non-corresponding isomers) are included within the scope of this invention.

[0088] Furthermore, the compounds of the present invention may be preferred compounds. The term "preferred compound" refers to those compounds that yield more desirable biological activity. For example, isomers and stereoisomers or mixtures of racemic or diastereomers of the compounds of the present invention, which are isolated, purified, or partially purified, are also included within the scope of the present invention. The purification and isolation of such materials can be achieved by standard techniques known in the art.

[0089] For example, a racemic mixture can be separated using conventional methods to obtain pure stereoisomers. For instance, optically active acids or bases can be used to form salts of diastereomers or covalently non-corresponding isomers. Suitable examples of acids are tartaric acid, diacetyl tartaric acid, benzoyl tartaric acid, and camphorsulfonic acid. Using methods well known to those skilled in the art, such as chromatography or fractional crystallization, mixtures of diastereomers can be separated into their individual non-corresponding isomers based on their physical and / or chemical differences. An optically active base or acid is then released from the salt of the separated diastereomers. Different methods for separating optical isomers include using chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, preferably selecting columns that adequately separate the enantiomers. Daicel manufactures suitable chiral HPLC columns, such as Chiracel OD and Chiracel OJ, and many other chiral HPLC columns are commonly chosen. Enzymatic separation is also used, with or without derivatization. Similarly, the optically active compounds of the present invention can also be obtained through chiral synthesis using optically active starting materials.

[0090] To restrict isomers that are different from each other, refer to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0091] It should be noted that the compounds of the present invention may also include all possible stereoisomers of the compounds of the present invention, which may be a single stereoisomer or any proportion of said stereoisomers, such as (R) or (S) isomers, or any mixture of (E) or (Z) isomers. The separation of single stereoisomers of the compounds of the present invention, such as single enantiomers or single non-corresponding isomers, can be achieved using any suitable method described in the art, such as chromatography, especially chiral chromatography.

[0092] Furthermore, the compounds of the present invention can exist in tautomer form. For example, any compound of the present invention containing a pyrazole moiety as a heteroaryl group can exist, for example, in the form of a 1H tautomer, a 2H tautomer, or a mixture of any number of the two tautomers; or containing a triazole moiety, for example, can exist in the form of a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture of any number of the 1H, 2H, and 4H tautomers, i.e.:

[0093]

[0094] It should be noted that the compounds of the present invention may also include all possible tautomers of the compounds of the present invention, as a single tautomer, or any mixture of said tautomers in any proportion.

[0095] Furthermore, the compounds of the present invention may exist in the form of N-oxides, defined as follows: at least one nitrogen atom in the compound of the present invention is oxidized. The present invention includes all such possible N-oxides.

[0096] It should be noted that the compounds of the present invention also relate to the available forms of the compounds disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and coprecipitates.

[0097] Furthermore, the compounds of the present invention can exist in the form of hydrates or solvates, wherein the compounds of the present invention contain a polar solvent, particularly water, methanol, or ethanol, for example, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, such as hydrates, they can be half (partial), one, one and a half, two, three, four, five solvates or hydrates, etc. The present invention includes all such hydrates or solvates.

[0098] Furthermore, the compounds of the present invention can exist in a free form, for example, as a free base or free acid or zwitterion, or can exist in the form of a salt. The salt can be any pharmaceutically acceptable salt, organic or inorganic addition salt, especially any pharmaceutically acceptable organic or inorganic addition salt.

[0099] In this document, the terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of a compound or its stereoisomers, formed with a relatively non-toxic inorganic and / or organic acid and base, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. Alternatively, they can be obtained by mixing the aforementioned compound, or its stereoisomers, with a suitable (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. Suitable pharmaceutically acceptable salts of the compounds of the present invention can be acid addition salts of basic compounds carrying nitrogen atoms in their chains or rings. In summary, those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by any of many known methods, through the reaction of said compound with a suitable inorganic or organic acid.

[0100] This invention includes salts of all possible compounds of the invention, as a single salt, or any mixture of said salts in any proportion.

[0101] Furthermore, this invention encompasses all possible crystalline forms or polymorphs of the compounds of this invention, as a single polymorph, or a mixture of more than one polymorph in any proportion. When substituting groups in the compounds of this invention, the groups may be mono- or polysubstituted, unless otherwise stated. Within the context of this invention, all groups appearing more than once are defined independently of each other. Preferably, they are substituted with one, two, or three identical or different substituents.

[0102] In this document, this disclosure also relates to compounds of general formula (I) or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or salts thereof (especially pharmaceutically acceptable salts), or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of hyperproliferative diseases. In this document, the term "hyperproliferative disease" includes, but is not limited to, for example: psoriasis, keloids and other proliferative disorders affecting the skin, benign prostatic hyperplasia (BPH), tumors such as breast cancer, respiratory cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. Those diseases also include lymphoma, sarcoma, and leukemia.

[0103] In this document, this disclosure further relates to compounds of general formula (I) or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or salts thereof (especially pharmaceutically acceptable salts), or pharmaceutical compositions comprising thereof, for the prevention and / or treatment of tumors. The term "tumor" includes, but is not limited to, melanoma, brain tumors, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumors, bladder cancer, and gallbladder cancer.

[0104] In this document, the term "treatment" or "treating" includes the suppression, delay, examination, relief, reduction, limitation, decrease, repression, resistance, or cure of a disease (the term "disease" includes, but is not limited to, symptoms, ailments, injuries, or health problems), or the development, progression, or development of such a state and / or the symptoms of such a state. The term "therapeutic method" is understood herein to be synonymous with the term "treatment."

[0105] In this document, the terms “prevention,” “prophylaxis,” or “preclusion” are used synonymously in the context of this invention and refer to avoiding or reducing the risk of infection, experiencing, having, or possessing a disease, or the development or progression of such a state and / or symptoms of such a state. Treatment or prevention of disease can be partial or complete.

[0106] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Detailed Implementation

[0107] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0108] General synthesis method 1:

[0109] When R 1 for R 2 for Compound (Ia) can also be synthesized by referring to the following steps:

[0110]

[0111] First, compound 1 is reacted with ethylene glycol and pyridine p-toluenesulfonate to give compound 2; compound 2, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, and triethylamine are reacted under carbon monoxide protection to give compound 3; compound 3 is reacted with m-chloroperoxybenzoic acid and dichloromethane to give compound 4; compound 4 is then reacted with a compound containing R... 2 The borate ester of the group, Pd(dppf)Cl2, and K2CO3 react under nitrogen protection to give compound 5; compound 5 reacts with triethylamine and POCl3 to give compound 6; compound 6 reacts with NH2NH2·H2O and is lyophilized to give compound 7; compound 7 reacts with N,N-diisopropylethylamine and ditert-butyl dicarbonate to give compound 8; compound 8 reacts with 3-methylmorpholine under microwave conditions to give compound 9; compound 9 reacts with POCl3 to give compound 10; compound 10 reacts with a compound containing R... 1 Boric acid, Pd(dppf)Cl2, and K2CO3 with the group were reacted under nitrogen protection to give compound 11; compound 11 was reacted with trifluoromethanesulfonic acid and trifluoroacetic acid to give the compound shown in formula (Ia).

[0112] General synthesis method 2:

[0113] When R 1 for R 2 for Compound (Ia) can also be synthesized by referring to the following steps:

[0114]

[0115] First, compound 9 (the synthesis of compound 9 is described in General Synthesis Method 2 for compound 9) was reacted with POCl3 to give compound 10; compound 10 was reacted with triethylamine and Pd(dppf)Cl2 under the protection of carbon monoxide to give compound 11; compound 11 was reacted with methanol and ammonia to give compound 12; compound 12 was reacted with (MeO)2CHNMe2 to give compound 13; compound 13 was reacted with NH2NH2·H2O and acetic acid to give the compound shown in formula (Ia).

[0116] General synthesis method 3:

[0117] When R 1 for R 2 for Compound (Ib) can also be synthesized using the following steps:

[0118]

[0119] First, compound 0 is combined with compound R. 1 Boric acid, K2CO3, and Pd(dppf)Cl2 with a radical group react under nitrogen protection to give compound 1; compound 1 reacts with Pd(dppf)Cl2, triethylamine, and methanol under nitric oxide pressure to give compound 2; compound 2 reacts with acetic anhydride to give compound 3; compound 3 reacts with tetrahydrofuran and potassium tert-butoxide under nitrogen protection to give compound 4; compound 4 reacts with POCl3 to give compound 5; compound 5 reacts with 3-methylmorpholine and N-methylpyrrolidone under microwave conditions to give compound 6; compound 6 reacts with a radical containing R... 2 The borate ester of the group, K2CO3, and Pd(dppf)Cl2 react under nitrogen protection to give compound 7; compound 7 is reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to give the compound shown in formula (Ib).

[0120] General synthesis method 4:

[0121] When R 1 for R 2 for Compound (Ib) can also be synthesized using the following steps:

[0122]

[0123] First, compound 6 (the synthesis of compound 6 is described in General Synthesis Method 3 for compound 6) was reacted with compound a, potassium carbonate, Pd(dppf)Cl2, and dioxane under nitrogen protection to obtain compound 7; compound 7 was reacted with methanol and hydrochloric acid at room temperature to obtain compound 8; compound 8 was mixed with compound b, cesium carbonate, and CH3CN, and reacted after being replaced with nitrogen to obtain compound 9; compound 9 was reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain the compound shown in formula (Ib).

[0124] General synthesis method 5:

[0125] 1) When R 1 for R 2 for Compound (Ib) can also be synthesized using the following steps:

[0126]

[0127] First, compound 1 was reacted with bipinnatol borate in CuSO4 aqueous solution to give compound 2; compound 2 was reacted with SM2 (4-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-chloropyrimidin-5-amine), K2CO3, and Pd(dppf)Cl2 in 1,4-dioxane under nitrogen protection to give compound 3; compound 3 was reacted with sodium ethoxide to give compound 4; compound 4 was reacted with POCl3 to give compound 5; compound 5 was reacted with 3-methylmorpholine and N-methylpyrrolidone under microwave conditions to give Compound 6; Compound 6 was reacted with 1,4-dioxane and SeO2 to give compound 7; Compound 7 was reacted with methanol and NaBH4 at room temperature to give compound 8; Compound 8 was reacted with triethylamine and 4-toluenesulfonyl chloride at room temperature to give compound 9; Compound 9 was reacted with sodium methanesulfite and dimethylformamide at room temperature to give compound 10; Compound 10 was reacted with 1,2-dibromoethane, tetrabutylammonium bromide, and toluene in an alkaline environment to give compound 11; Compound 11 was reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to give the compound shown in formula (Ib). The structural formula of SM2 is shown below:

[0128]

[0129] 2) When R 1 for R 2 for Compound Ib can also be synthesized by referring to the following steps:

[0130] Compound 10 from step 1) was reacted with 1,4-dibromoethane, tetrabutylammonium bromide, and toluene in an alkaline environment to obtain compound 11; compound 11 was reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to obtain the compound shown in formula (Ib).

[0131] General synthesis method 6:

[0132] When R 1 for R 2 for Compound (Ib) can also be synthesized using the following steps:

[0133]

[0134] First, compound 8 (the synthesis of compound 8 is described in General Synthesis Method 5 for compound 8) was reacted with phosphorus tribromide at room temperature in anhydrous dichloromethane to give compound 9; compound 9 was reacted with sodium thiolate containing alkyl groups and dimethylformamide at room temperature to give compound 10; compound 10 was reacted with sodium periodate, ethyl acetate, and methanol at room temperature to give compound 11; compound 11 was reacted with trifluoroacetamide, PhI(AcO)2, MgO, and Rh2(OAc)4 under nitrogen protection to give compound 12; compound 12 was reacted with trifluoroacetic acid and trifluoromethanesulfonic acid to give the compound shown in formula (Ib).

[0135] General synthesis method 7:

[0136] When R 1 for R 2 for Compound (Ib) can also be synthesized using the following steps:

[0137]

[0138] First, compound 1 is combined with a compound containing R. 2 The borate ester of the group, potassium carbonate, and Pd(dppf)Cl2 were reacted under nitrogen protection to give compound 2; compound 2 was reacted with dimethyl sulfoxide and potassium tert-butoxide / tetrahydrofuran in an oxygen environment to give the compound shown in formula (Ib).

[0139] General synthesis method 8:

[0140] When R 1 for R 2 for Compound (Ic) can also be synthesized by referring to the following steps:

[0141]

[0142] First, compound 1 was reacted with benzyl bromide, cesium carbonate, and MeCN to give compound 2; compound 2 was mixed with compound 3, Pd(PPh3)2Cl2, cesium carbonate, and MeCN, and reacted after nitrogen purging to give compound 4; compound 4 was reacted with NH3 / methanol at room temperature to give compound 5; compound 5 was reacted with triphosgene to give compound 6; compound 6 was reacted with POCl3 and diisopropylethylamine to give compound 7; compound 7 was reacted with a compound containing R... 2The alkyl group, AlCl3, dichloromethane, and N-methylpyrrole were reacted to give compound 8; compound 8 was reacted with 3-methylmorpholine, diisopropylethylamine, and N-methylpyrrolidone to give compound 9; compound 9 was reacted with dimethyl sulfoxide and potassium tert-butoxide / tetrahydrofuran in an oxygen environment to give the compound shown in formula (Ic).

[0143] Example 1: Preparation of compound A-3

[0144]

[0145] The specific preparation steps of compound A-3 are as follows:

[0146] Compound 1 (24.5 g, 0.14 mol), ethylene glycol (87 g, 1.4 mol), pyridine p-toluenesulfonate (PPTS) (3.5 g, 0.014 mol), and 100 mL of toluene were added to a 250 mL single-necked flask. The mixture was reacted at 50 °C for 16 h, concentrated, and subjected to column chromatography (PE:EA = 8:1) to give 30 g of product 2, a colorless oil, with a yield of 97%. The retention time of the product in LC-MS O1 was 2.125 min, and the m / z (ESI) was 221.1 (M+H). + .

[0147] Compound 2 (30 g, 0.14 mol) was dissolved in 100 mL of methanol (MeOH), followed by the addition of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (Pd(dppf)Cl2) (3.1 g, 4.2 mmol) and triethylamine (TEA) (28.5 g, 0.28 mol). The reaction was carried out overnight at 60 °C under carbon monoxide (CO) protection. The mixture was concentrated and subjected to column chromatography (PE:EA = 5:1) to give 29 g of product 3, a white solid, in 87% yield. The retention time of the product in LC-MS O2 was 1.952 min, m / z (ESI) = 243.8 (M+H). + .

[0148] Compound 3 (29 g, 0.12 mol) was dissolved in 100 mL of dichloromethane (DCM), and m-chloroperoxybenzoic acid (m-CPBA) (41 g, 0.24 mol) was added. The mixture was reacted overnight at 25 °C, filtered, concentrated, and subjected to column chromatography (PE:EA = 3:1) to give 30 g of product 4, a white solid, in 96% yield. The retention time of the product in LC-MS O3 was 2.088 min, m / z (ESI) = 259.8 (M+H). + .

[0149] Compound 4 (30 g, 0.12 mol) and its borate ester (50 g, 0.24 mol) were dissolved in 200 mL of dioxane and 20 mL of H₂O. Pd(dppf)Cl₂ (2.6 g, 3.6 mmol) and K₂CO₃ (33 g, 0.24 mol) were then added. The reaction mixture was reacted at 100 °C for 2 h under nitrogen (N₂) protection. The reaction solution was filtered, concentrated, and subjected to column chromatography (PE:EA = 3:1) to give 20 g of product 5 as a yellow solid, with a yield of 55%. The retention time of the product in LC-MS O₄ was 1.783 min, m / z (ESI) = 305.8 (M+H). + .

[0150] Compound 5 (20 g, 62.6 mmol) and TEA (63 g, 626 mmol) were dissolved in 100 mL of DCM. POCl3 (50 g, 323 mmol) was added under ice bath conditions, and the reaction was carried out overnight at 25 °C. TEA was added to adjust the pH of the reaction solution to 8-9. The solution was concentrated, and column chromatography (PE:EA = 5:1) yielded 4 g of product 6 as a yellow solid, with a yield of 20%. The retention time of the product in LC-MS O5 was 2.164 min, m / z (ESI) = 323.8 (M+H). + .

[0151] Compound 6 (4 g, 12.4 mmol) was dissolved in 15 mL of ethanol (EtOH), and then NH₂NH₂·H₂O (6.2 g, 124 mmol) was added. The reaction was carried out overnight at 25 °C. The reaction solution was lyophilized to give 3 g of product 7, a yellow solid, with a yield of 75%. The retention time of the product in LC-MS O6 was 1.614 min, m / z (ESI) = 323.7 (M+H). + .

[0152] Compound 7 (3 g, 9.3 mmol) and N,N-diisopropylethylamine (DIEA) (2.4 g, 18.6 mmol) were dissolved in 20 mL of DCM, and then di-tert-butyl dicarbonate ((Boc)₂O) (4.1 g, 18.6 mmol) was added. The mixture was reacted overnight at 25 °C. 10 mL of H₂O was added, and the mixture was extracted with DCM, dried, concentrated, and subjected to column chromatography (PE:EA = 2:1) to give 2.5 g of product 8 as a yellow solid, in 63% yield.

[0153] Compound 8 (2.5 g, 5.9 mmol) was placed in a microwave-safe tube, and morpholine (3 mL) was added. The reaction was carried out in a microwave oven at 150 °C for 4 h. The reaction solution was lyophilized and subjected to column chromatography (DCM:MeOH = 40:1) to give 800 mg of product 9 as a yellow solid, with a yield of 41%. The retention time of the product in LC-MS O9 was 1.950 min, and the m / z (ESI) was 326.9 (M+H).+ .

[0154] Compound 9 (200 mg, 0.61 mmol) was dissolved in POCl3 (10 mL), reacted at 100 °C for 2 h, concentrated, and then directly proceeded to the next reaction step. The retention time of the product in LC-MS 10 was 2.475 min, m / z (ESI) = 344.8 (M+H). + .

[0155] Unpurified compound 10 was dissolved in 20 mL of Dioxane, and K₂CO₃ (1.7 g, 12.2 mmol) and 2 mL H₂O were added to ensure the reaction solution was alkaline. Boric acid (283 mg, 1.22 mmol) and Pd(dppf)Cl₂ (44 mg, 0.06 mmol) were then added. The reaction was carried out at 100 °C for 2 h under nitrogen protection. The solution was concentrated and subjected to column chromatography (DCM:MeOH = 40:1) to give 150 mg of product 11 as a yellow solid, with a two-step yield of 49%. LC-MS showed that the product 11 had a retention time of 2.533 min and an m / z (ESI) of 497.2 (M+H). + .

[0156] Compound 11 (150 mg, 0.30 mmol) was dissolved in trifluoroacetic acid (TFA) (2.5 mL), followed by the addition of trifluoromethanesulfonic acid (TfOH) (0.5 mL). The reaction mixture was reacted at 45 °C for 4 h. The pH of the reaction solution was adjusted to 8-9 by adding saturated sodium bicarbonate solution. The mixture was extracted with DCM, dried, and concentrated. Pre-HPLC purification yielded 30 mg of product A-3 as a yellow solid, with a yield of 27%. The retention time of the product in LC-MS was 1.645 min, m / z (ESI) = 376.8 (M+H). + . 1 H NMR (400MHz, DMSO-d6δ13.77(s,1H),8.96(s,1H),7.81–7.62(m,3H),7.49(s,1H),6.70(d,J=1.6Hz,1H),4.73(s,1H),4.3 6(d,J=13.3Hz,1H),4.04(t,J=11.4Hz,1H),3.83(s,4H),3.71(d,J=10.7Hz,1H),3.62–3.50(m,2H),1.33(d,J=6.5Hz,3H).

[0157] Example 2: Preparation of compound A-2

[0158]

[0159] The specific preparation steps of compound A-2 are as follows:

[0160] Compound 9 (preparation of compound 9 is described in Example 1) (350 mg, 1.07 mmol) was dissolved in POCl3 (10 mL), reacted at 100 °C for 2 h, concentrated, and then directly proceeded to the next reaction step. The retention time of the product in LCMS-1 was 2.475 min, m / z (ESI) = 344.8 (M+H). + .

[0161] Unpurified compound 10 was dissolved in 10 mL of MeOH, and 2 mL of TEA was added to ensure the reaction solution was alkaline. Then, Pd(dppf)Cl2 (78 mg, 0.11 mmol) was added. The reaction was carried out at 60 °C for 16 h under carbon monoxide protection. The solution was concentrated and subjected to column chromatography (DCM:MeOH = 60:1) to give 270 mg of product 11 as a yellow solid. The two-step yield was 68%. The retention time in LCMS-2 was 1.912 min, and the m / z (ESI) was 368.8 (M+H). + .

[0162] Compound 11 (270 mg, 0.73 mol) was dissolved in 7 M NH3 / MeOH (10 mL) in a sealed tube and reacted at 40 °C for 16 h. The solution was concentrated to give 240 mg of crude product 12, a white solid, with a yield of 93%. The retention time of the product in LCMS-3 was 1.952 min, and the m / z (ESI) was 353.8 (M+H). + .

[0163] Compound 12 (240 mg, 0.68 mmol) was dissolved in 0.5 mL of (MeO)₂CHNMe₂ and placed in a sealed tube. The reaction was carried out at 95 °C for 15 min, and the product was concentrated to give 200 mg of crude product 13, a white solid, with a yield of 72%. The retention time of the product in LCMS-4 was 1.596 min, and the m / z (ESI) was 408.8 (M+H). + .

[0164] Compound 13 (200 mg, 0.49 mmol) was dissolved in 2 mL of CH3COOH, followed by the addition of NH2NH2·H2O (49 mg, 0.98 mmol). The reaction was carried out at 90 °C for 1.5 h. Pre-HPLC purification yielded 60 mg of product A-2 as a yellow solid, with a yield of 33%. The retention time of the product in LCMS was 1.961 min, and the m / z (ESI) was 378.2 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ14.47(s,1H),9.14–8.95(m,1H),8.44(s,1H),7.76–7 .55(m,2H),6.76–6.69(m,1H),4.64(s,1H),4.40(d,J=11.8Hz,1H),4.03–3.92 (m,1H),3.89–3.82(m,3H),3.76(d,J=11.7Hz,1H),3.64(dd,J=11.5,2.8Hz,1H ), 3.49 (td, J = 11.9, 2.7Hz, 1H), 3.25 (d, J = 12.6Hz, 1H), 1.24 (d, J = 6.7Hz, 3H).

[0165] The preparation of compounds A-4, A-5, A-6, A-7, A-8, and A-9 followed the synthesis of compound A-3 in Example 1. The structural formulas and NMR characterization results of compounds A-4, A-5, A-6, A-7, A-8, and A-9 are shown in Table 1.

[0166] Table 1: Structural formulas and NMR characterization results of compounds A-4, A-5, A-6, A-7, A-8 and A-9

[0167]

[0168]

[0169] Example 3: Preparation of compound B-2 / B-2a

[0170]

[0171] The specific preparation steps for compound B-2 / B-2a are as follows:

[0172] Compound O (10 g, 61 mmol), (1-(4-methoxybenzyl)-1H-pyrazol-3-yl)boronic acid (21 g, 92 mmol), K₂CO₃ (17 g, 122 mmol), and Pd(dppf)Cl₂ (450 mg) were added to a 200 mL single-necked flask, followed by 5 mL of water. The reaction was carried out overnight at 100 °C under N₂ protection. The reaction was monitored by LC-MS, and the product was purified by column chromatography (PE:EA = 6:1) to give 9 g of a yellow oily product (yield 47%). m / z (ESI) = 315.8 (M+H) + .

[0173] 5.8 g (18.4 mmol), Pd(dppf)Cl2 (135 mg, 0.18 mmol), and TEA (3.7 g, 37 mmol) were dissolved in 100 mL of anhydrous MeOH. The solution was replaced with CO and reacted overnight at 50 °C under CO pressure. The reaction was monitored by LC-MS, and the product was purified by column chromatography (PE:EA = 1:1) to give 3.2 g of product (yield 51.34%). m / z (ESI) = 339.9 (M+H) + .

[0174] Compound 2 (3 g, 8.85 mmol) was dissolved in 20 mL of acetic anhydride and reacted overnight at 100 °C. The reaction was monitored by LC-MS, and the product was purified by column chromatography (PE:EA = 2:1) to give 2.7 g of product (yield 72.13%). m / z (ESI) = 423.7 (M+H) + .

[0175] Compound 3 (2.7 g, 6.4 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran (THF), and potassium tert-butoxide (t-BuOK) (2.2 g, 19.2 mmol) was added. The reaction was carried out at 80 °C for 3 h under N2 protection. The reaction was monitored by LC-MS, and the product was purified by column chromatography (DMC:MeOH = 10:1) to give 1.5 g of product (yield 67.34%). m / z (ESI) = 350.1 (M+H) + .

[0176] Compound 4 (1.5 g, 4.3 mmol) was dissolved in 20 mL of POCl3 and reacted at 100 °C for 3 h. The reaction was monitored by LC-MS, and the product was purified by column chromatography (DMC:MeOH = 10:1) to give 1 g of product (yield 60.3%). m / z (ESI) = 385.7 (M+H) + .

[0177] Compound 5 (1 g, 2.6 mmol) was dissolved in 2 mL of 3-methylmorpholine, and a small amount of N-methylpyrrolidone (NMP) was added to aid dissolution. The mixture was microwaved at 100 °C for 3 h. The reaction was monitored by LC-MS. After freeze-drying to remove NMP and 3-methylmorpholine, the mixture was purified by column chromatography (PE:EA = 2:1) to obtain a total of 500 mg of products 6 and 6a (yield 42.83%). On LC-MS, the product peak was at a molecular weight of 450.8, with an elution time of 2.3 min for product 6 and 2.55 min for product 6a.

[0178] 500 mg (1.11 mmol) of compounds 6 and 6a, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-1H-pyrazole (700 mg, 3.33 mmol), K₂CO₃ (300 mg, 2.22 mmol), and Pd(dppf)Cl₂ (73 mg, 0.1 mmol) were dissolved in 10 mL of 1,4-dioxane and 2 mL of water. The reaction was carried out overnight at 100 °C under N₂ protection. The reaction was monitored by LC-MS, and the product compound 7 (140 mg) + compound 7a (60 mg) were separated and purified by column chromatography (PE:EA = 1:1) (overall yield 36.3%), m / z (ESI) = 497 (M+H). + .

[0179] Compound 7 (140 mg) was dissolved in 2.5 mL of trifluoroacetic acid (TFA), and then added to 0.5 mL of trifluoromethanesulfonic acid (TfOH). After reacting at 40 °C for 3 h, the reaction was monitored by LC-MS until complete. The mixture was neutralized with saturated NaHCO3 solution, extracted with DCM, and the DCM was removed by vacuum distillation. The product was then dissolved in dimethyl sulfoxide (DMSO) for liquid-phase purification to obtain 20 mg (yield 18.9%) of the target product B-2. 1H NMR (400MHz, CDCl3) δ9.11(s,1H),7.77(d,J=1.8Hz,1H),7.65(d,J=1.8Hz,1H),7.47(d,J=1.9H z,1H),7.37(s,1H),6.51(d,J=1.9Hz,1H),4.44(dd,J=6.7,2.3Hz,1H),4.19(dd,J=11.5,3.7Hz, 1H),4.05(dd,J=12.8,2.2Hz,1H),3.94(d,J=11.6Hz,1H),3.86(dd,J=11.6,3.0Hz,1H),3.82(d, J=3.6Hz, 3H), 3.73 (td, J=11.8, 3.0Hz, 1H), 3.58 (td, J=12.5, 3.9Hz, 1H), 1.48 (d, J= 6.8Hz, 3H).

[0180] Compound 7a (60 mg) was dissolved in 2.5 mL of TFA and added to 0.5 mL of TfOH. After reacting at 40 °C for 3 h, the reaction was monitored by LC-MS to ensure complete reaction. The mixture was neutralized with saturated NaHCO3 solution, extracted with DCM, and the DCM was removed by vacuum distillation. The product was then dissolved in DMSO for liquid-phase purification to obtain 10 mg (yield 21.9%) of the target product B-2a. 1H NMR (400MHz, CDCl3) δ9.20(s,1H),7.75(d,J=1.9Hz,1H),7.62(d,J=1.9Hz,1H),7.49(t,J=2.2Hz,1H),7.11(s,1H),6.67(dd,J=6.2,2.0Hz,1H ), 5.29 (s, 1H), 4.25–4.22 (m, 3H), 4.14–4.05 (m, 2H), 3.88 (ddd, J = 25.5, 17.2, 7.1Hz, 3H), 3.67 (td, J = 12.2, 3.6Hz, 1H), 1.32 (t, J = 5.8Hz, 4H).

[0181] Example 4: Preparation of compound B-3

[0182]

[0183] The specific preparation steps for compound B-3 are as follows:

[0184] Compound 1 (25 g, 255 mmol) and bipinnatol borate (44 g, 173 mmol) were dissolved in an aqueous solution of CuSO4 (408 mg, 2.55 mmol) at a concentration of 1.3 mg / mL. Then, 4-methylpyridine (1.2 g, 12.75 mmol) was added, and the mixture was heated to 50 °C. Bipinnatol borate (44 g, 173 mmol) was then added, and the mixture was stirred at 50 °C for 3 h. After the reaction was complete as monitored by TLC, it was extracted with EA to give 55 g of the product (yield 57.28%) (60% purity).

[0185] Compound 2 (55 g, 243 mmol), SM2 (26 g, 81 mmol), K2CO3 (22 g, 162 mmol), and Pd(dppf)Cl2 (600 mg, 0.81 mmol) were dissolved in 200 mL of 1,4-dioxane and reacted overnight at 100 °C under N2 protection. The reaction was monitored by LC-MS, and the product was purified by column chromatography (petroleum ether (PE): ethyl acetate (EA) = 2:1) to give 35 g of product (yield 63.2%), m / z (ESI) = 380.2 (M+H). + .

[0186] Compound 3 (35 g, 92 mmol) was dissolved in 200 mL of EtOH, and sodium ethoxide (EtONa) (8 g, 116 mmol) was added. The reaction was carried out overnight at 80 °C. The reaction was monitored by LC-MS, and the product was purified by column chromatography (PE:EA = 1:1) to give 25 g of product (yield 78.02%), m / z (ESI) = 347.8 (M+H). +Compound 4 (25 g, 72 mmol) was dissolved in 100 mL of POCl3 and reacted at 100 °C for 3 h. After removing most of the POCl3 by vacuum distillation, saturated NaHCO3 solution was slowly added under ice bath to neutralize the solution. The solution was then purified by column chromatography (PE:EA = 1:1) to obtain 17 g of yellow solid (yield 64.57%).

[0187] Compound 5 (17 g, 46.6 mmol) was dissolved in 20 mL of 3-methylmorpholine, with a small amount of NMP added for dissolution. The mixture was reacted by microwave at 130 °C for 2 h. The reaction was monitored by LC-MS. 3-methylmorpholine and NMP were removed by freeze-drying. The product was purified by column chromatography (DMC:MeOH = 20:1) to give 12 g of product (yield 59.98%), m / z (ESI) = 385.7 (M+H). + .

[0188] Compound 6 (12 g, 28 mmol) was dissolved in 100 mL of 1,4-dioxane, and SeO2 (6.2 g, 56 mmol) was added. The mixture was reacted overnight at 100 °C. LC-MS monitoring showed the presence of the target product, along with a small amount of carboxylic acid product. Column chromatography (PE:EA = 1:1) was used to separate and purify the product, yielding 8 g (64.57%), m / z (ESI) = 444.8 (M+H). + .

[0189] Compound 7 (8 g, 18 mmol) was dissolved in 100 mL of MeOH, and NaBH4 (2 g, 54 mmol) was slowly added under ice bath conditions. The reaction was carried out at room temperature for 3 h. The reaction was monitored by LC-MS, and the product was purified by column chromatography (PE:EA = 1:1) to give 5 g of product (yield 62.22%), m / z (ESI) = 446 (M+H). + .

[0190] Compound 8 (5 g, 11.2 mmol) and TEA (2.3 g, 22.4 mmol) were dissolved in 30 mL of DCM, and 4-toluenesulfonyl chloride (TsCl) (3.2 g, 16.8 mmol) was added. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by LC-MS. The reaction was quenched with water, extracted with EA, washed with saturated NaHSO4 and NaCl solutions, and the product was dried over anhydrous MgSO4. 3.8 g of the product (yield 56.49%) was obtained.

[0191] Compound 9 (3.8 g, 6.3 mmol) and sodium methanesulfite (1.3 g, 12.6 mmol) were dissolved in 20 mL of dimethylformamide (DMF) and reacted overnight at room temperature. The reaction was monitored by LC-MS. After removing DMF by vacuum distillation, the product was purified by column chromatography (DCM:MeOH = 10:1) to give 2.1 g of product (yield 65.27%).

[0192] Compound 10 (300 mg, 0.6 mmol), 1,2-dibromoethane (222 mg, 1.2 mmol), and tetrabutylammonium bromide (TBAB) (40 mg, 0.12 mmol) were dissolved in 3 mL of toluene, and then 1 mL of 50% NaOH solution was added. The reaction was carried out overnight at 60 °C. The reaction was monitored by LC-MS. Toluene and water were removed by vacuum distillation, and 200 mg of the purified product (63.42% yield) was separated by column chromatography (PE:EA = 1:1).

[0193] Compound 11 (200 mg) was dissolved in TFA (2.5 mL) and TfOH (0.5 mL), and reacted at 40 °C for 3 h. The reaction was monitored by LCMS to ensure complete reaction. The solution was neutralized with saturated NaHCO3 solution in an ice bath, extracted with DCM, evaporated to dryness, and then dissolved in DMSO for liquid chromatography to obtain 31.04 mg of product B-3 (yield 19.99%). 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.85(s,1H),7.71(s,1H),7.58(s,1H),4.63(s,1H),4.23(d,J=13.1Hz,1H),4.07(d,J=8.2Hz,1H),3.84(d,J =11.5Hz,1H),3.72(d,J=9.3Hz,1H),3.57(t,J=10.5Hz,1H),3.38(s,1H) ,3.02(s,3H),1.86(q,J=5.2Hz,2H),1.52(s,2H),1.30(d,J=6.6Hz,3H).

[0194] Example 5: Preparation of compound B-4

[0195]

[0196] The specific preparation steps of compound B-4 are as follows:

[0197] Compound 1 (3.2 g) was dissolved in 20 mL of anhydrous dichloromethane. Phosphorus tribromide (4.0 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to warm naturally to room temperature and stirred for 3 hours. The reaction was monitored by LCMS until complete. The reaction solution was poured into 100 mL of ice water, and sodium carbonate was slowly added to adjust the pH to 7-8. After extraction with dichloromethane (100 mL × 2), the organic phases were combined, dried, filtered, and rotary evaporated to obtain 4.2 g of crude oil, which was used directly in the next step.

[0198] Compound 2 (4.2 g, crude) was dissolved in 25 mL of DMF, and 1.7 g of sodium methanethiol was added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred overnight (16 hours). The reaction solution was extracted with dichloromethane (100 mL × 2), the organic phases were combined, dried, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by column chromatography (EA / PE = 100 / 0-0 / 100) to give 900 mg of yellow solid compound 3. The two-step yield was 26.35%.

[0199] Compound 3 (450 mg) was dissolved in ethyl acetate (4 mL), methanol (2 mL), and water (2 mL), and then sodium periodate (202 mg, 1.0 eq) was added. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS until complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 100 / 0-90 / 10, 20 min) to give 350 mg of yellow solid compound 4, with a yield of 75.3%.

[0200] Compound 4 (380 mg, 0.77 mmol), trifluoroacetamide (174 mg, 1.54 mmol), PhI(AcO)₂ (273 mg, 0.85 mmol), MgO (124 mg, 3.08 mmol), and Rh₂(OAc)₄ (10.2 mg, 0.023 mmol) were dissolved in 8 mL of anhydrous dichloromethane. The mixture was stirred at room temperature under nitrogen protection for 16 hours. LC-MS monitoring showed that about half of the starting material remained. The reaction mixture was evaporated to dryness and purified by a neutral alumina column (using pure ethyl acetate) to give 210 mg of compound 5 with a purity of 40%, which was used directly in the next step.

[0201] Compound 5 (210 mg, 40% purity) was placed in a 100 mL single-necked flask, and trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (1 mL) were added. The flask was sealed and stirred at 50 °C for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was poured into 100 mL of ice water, and sodium carbonate solid was slowly added to adjust the pH of the solution to 7-8. After extraction with dichloromethane (50 mL × 2), the organic phases were combined, dried, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by liquid chromatography to obtain 10 mg of a pale yellow solid compound B-4, with a yield of 18.6%. 1H NMR (400MHz, CDCl3) δ12.70(s,1H),9.09(s,1H),7.76(d,J=1.9Hz,1H),7.60(s,1H),7.44(d,J=1.9H z,1H),5.08(dd,J=13.2,6.6Hz,1H),4.88(dd,J=13.2,6.7Hz,1H),4.44(d,J=6.6Hz,1H),4.17(dd,J =11.5,3.8Hz,1H),4.05(d,J=12.8Hz,1H),3.93(d,J=11.6Hz,1H),3.85(dd,J=11.6,3.0Hz,1H),3.7 1(td,J=12.0,3.1Hz,1H),3.59–3.50(m,1H),2.96(s,3H),2.91–2.77(m,1H),1.46(d,J=6.8Hz,3H).

[0202] Example 6: Preparation of compound B-8

[0203]

[0204] The specific preparation steps for compound B-8 are as follows:

[0205] Compound 1 (25 g, 71.5 mmol), POCl3 (150 ml), and diisopropylethylamine (DIPEA) (10 drops) were added to a 500 ml single-necked flask and reacted at 110 °C for 3 hours. The reaction was monitored by LC-MS, and the product was purified by rotary evaporation with DCM and PE / EA ratio of 3:1 to obtain product 2 (20 g, 72.36%) as a yellow powder, m / z (ESI) = 386 (M+H). + .

[0206] Compound 2 (3.5 g, 9 mmol) was added to DIEA (12 ml), followed by 3-(S)-3-methylmorpholine (3 ml). The reaction vessel was a microwave-safe tube. After purging with nitrogen, the reaction mixture was microwaved at 120 °C for 2 hours. The reaction was monitored by LC-MS. The reaction solution was extracted with DCM / saturated ammonium chloride solution at a PE:EA ratio of 2:1 to obtain product 3 (1.5 g, 36.7%) as a yellow powder. The peak position in LC-MS was 2.72 min, m / z (ESI) = 451 (M+H). + .

[0207] Compound 3 (1.5 g, 3.3 mmol) was dissolved in dioxane (15 ml) and purified water (2 ml). Starting material 4 (980 mg, 5 mmol), potassium carbonate (920 mg, 6.6 mmol), and Pd(dppf)Cl2 (120 mg, 0.16 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen protection. The reaction was monitored by LC-MS. The product 5 (700 mg, 37.1%) was purified by column chromatography with a PE / EA ratio of 1:1 after rotary evaporation. The peak position in the LC-MS was 2.98 min, and the m / z (ESI) was 567 (M+H). + .

[0208] Compound 5 (300 mg) was dissolved in 5 ml of methanol hydrochloric acid and added to a 50 ml single-necked flask. The mixture was stirred overnight at room temperature, evaporated to dryness, extracted with DCM, dried, filtered, and evaporated to dryness. The crude product 6 (250 mg) was then used directly in the next step of the reaction.

[0209] Compound 6 (250 mg, 0.51 mmol) was added to CH3CN (6 mL), followed by starting material 7 (296 mg, 1.04 mmol) and cesium carbonate (500 mg, 1.55 mmol) in a 50 mL single-necked flask. The mixture was purged with nitrogen and heated to 40 °C with stirring overnight. The reaction was monitored by LC-MS. After filtration, the sample was stirred under dry conditions and filtered through a PE:EA ratio of 10:1 to obtain product 8 (120 mg, 36.1%) as a yellow powder. The peak position in LC-MS was 3.18 min, m / z (ESI) = 640 (M+H). + .

[0210] Raw material 8 (120 mg, 0.18 mmol), trifluoroacetic acid (2.5 ml), and trifluoromethanesulfonic acid (0.5 ml) were added to a 50 ml single-necked flask and reacted at 40 °C for 1.5 h. The reaction was monitored by LC-MS. The reaction solution was neutralized with saturated sodium bicarbonate solution. After DCM extraction, the product B-8 (20 mg, 26.28%) was prepared and purified by HPLC as a yellow powder. 1H NMR (400MHz, CDCl3) δ8.99(s,1H),7.84(s,1H),7.66(d,J=1.8Hz,1H),7.52(d,J=2.2Hz,1H),7.39 (d,J=2.2Hz,1H),7.32(d,J=1.8Hz,1H),4.39(d,J=4.7Hz,1H),4.32–4.26(m,2H),4.10(dd,J=11.5 ,3.6Hz,1H),4.05–4.00(m,2H),3.95(dd,J=12.8,2.2Hz,1H),3.86(d,J=11.5Hz,1H),3.81(d,J=2 .8Hz,1H),3.65(d,J=2.9Hz,1H),3.45(d,J=3.9Hz,1H),1.37(d,J=6.8Hz,3H); m / z(ESI)=323(M+H) + .

[0211] Example 7: Preparation of compound B-18

[0212]

[0213] The specific preparation steps for compound B-18 are as follows:

[0214] Compound 10 (see the synthesis of compound B-3) (200 mg, 0.4 mmol), 1,4-dibromobutane (169 mg, 0.8 mmol), and TBAB (25 mg, 0.08 mmol) were dissolved in 2 mL of toluene. Then, 1 mL of 50% NaOH solution was added, and the mixture was reacted overnight at 60 °C. A product peak was observed by LC-MS. Toluene and water were removed by vacuum distillation, and the purified product (110 mg, yield 49.71%) was separated by column chromatography (PE:EA = 1:1).

[0215] Compound 11 (110 mg) was dissolved in TFA (2.5 mL) and TfOH (0.5 mL), and reacted at 40 °C for 3 h. The reaction was monitored by LCMS to ensure complete reaction. The solution was neutralized with saturated NaHCO3 solution in an ice bath, extracted with DCM, evaporated to dryness, and then dissolved in DMSO for liquid chromatography to obtain 26 mg of product (yield 30.0%). 1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.71(s,1H),7.60(s,1H),7.56(s,1H),4.61(d,J=4.9Hz,1 H),4.20(d,J=12.2Hz,1H),4.07(d,J=8.8Hz,1H),3.84(d,J=11.4Hz,1H),3.73(dd,J=12.5,3.3H z,1H),3.58(dd,J=11.7,9.3Hz,1H),3.38(dd,J=7.5,3.7Hz,1H),3.10(dd,J=13.3,7.2Hz,2H), 2.86(s,3H),2.81–2.66(m,2H),1.98–1.87(m,2H),1.69(d,J=2.1Hz,2H),1.28(d,J=6.7Hz,3H).

[0216] Example 8: Preparation of compound B-1

[0217]

[0218] The specific preparation steps of compound B-1 are as follows:

[0219] Compound 1 (75 mg, 0.17 mmol) was added to a mixed solution of dioxane (10 mL) and water (1 mL), followed by the addition of potassium carbonate (47 mg, 0.34 mmol), Pd(dppf)Cl2 (62 mg, 0.08 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)-1H-pyrazole (71 mg, 0.34 mmol). The reaction was carried out at 100 °C for 3 hours under nitrogen protection. After the reaction was complete, the sample was purified by column chromatography (DCM:MeOH = 30:1) with dry stirring to give a yellow solid product (50 mg, 61%). (ESI) m / z = 480.3 (M+H) + ,t=2.443min(215nm).

[0220] Compound 2 (50 mg, 0.10 mmol) was dissolved in 1 M t-BuOK / THF (2 ml), and then DMSO (1.5 ml) was added to the mixture in a 100 ml three-necked flask. Oxygen was bubbled in while stirring for about 10 min. LC-MS monitoring showed that the reaction was at 50%. Then, DMSO and 1 M t-BuOK / THF were added, and oxygen was bubbled in for another 10 min. LC-MS monitoring showed that the reactant concentration decreased while the product concentration increased, but some reactant remained unreacted. The product was then evaporated to dryness to obtain a yellow solid product (5 mg, 13%). 1H NMR (400MHz, CDCl3) δ7.76(s,1H),7.63(s,1H),7.46(s,1H),7.33(s,1H),6.49(s,1H) ,5.72(s,2H),4.41(d,J=6.3Hz,1H),4.18(dd,J=11.4,3.1Hz,1H),4.01(d,J=12.7Hz, 1H),3.93(d,J=11.5Hz,1H),3.87(s,1H),3.83(d,J=0.8Hz,3H),3.76–3.67(m,1H),3. 55(td,J=12.5,3.4Hz,1H),2.80(s,3H),1.46(d,J=6.8Hz,4H).(ESI)m / z=391.2(M+H) + ,t=1.896min(215nm).

[0221] The preparation of compounds B-5, B-6, B-7, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-19, B-20, B-21, B-22, B-23, B-24, B-25 and B-26 was carried out in accordance with the synthesis of compound B-2 in Example 3. Their structural formulas and NMR characterization results are shown in Table 2.

[0222] Table 2: Structural formulas and NMR characterization results of each compound

[0223]

[0224]

[0225]

[0226] Example 9: Preparation of compound C-1

[0227]

[0228] The specific preparation steps of compound C-1 are as follows:

[0229] Compound 1 (2g), benzyl bromide (1.3ml), cesium carbonate (10.1g) and 80ml of MeCN were added to a 250ml single-necked flask and reacted at 100℃ for 2h. The reaction was monitored by LC-MS. The reaction solution was used directly for the next reaction without any treatment.

[0230] Compound 3 (methyl 3-amino-2-chloro-pyridine-4-carboxylic acid ester) (1.5 g), Pd(PPh3)2Cl2 (723 mg), and 3 mL of water were added to the reaction solution from the first step. The mixture was purged with nitrogen and reacted overnight at 100 °C. The reaction was monitored by LC-MS. The product was evaporated to dryness with DCM and filtered out at a PE:EA ratio of 10:1 to give 1.0 g of compound 4, with a yield of 31.5% and m / z (ESI) = 308 (M+H). + .

[0231] Compound 4 (3g) and 30ml of 7M NH3 / MeOH were added to a 48ml sealed tube and reacted for 3 days. LC-MS monitoring showed that most of the starting material did not participate in the reaction. Column chromatography (PE / EA) separated the product and the starting material. The starting material was then added to 7M NH3 / MeOH for further reaction, finally yielding a yellow solid compound 5 (708mg) with a yield of 27.33%.

[0232] Compound 5 (500 mg) and triphosgene (506 mg) were added to 30 mL of THF and reacted overnight at 70 °C in a 100 mL single-necked flask. The reaction was monitored by LC-MS until complete, and the crude compound 6 was obtained by rotary evaporation with 624 mg of crude compound 6, m / z (ESI) = 319 (M+H). + This can be used directly in the next step.

[0233] Compound 6 (400 mg), POCl3 (6 ml), and DIPEA (4 drops) were added to a 10 ml microwave tube and reacted overnight at 110 °C. Since the product is extremely unstable and reacts with water or alcohol, the product was directly evaporated to dryness before being added to the next reaction step.

[0234] Compound 7 (400 mg) and AlCl3 (360 mg) were added to a 30 mL DCE in a three-necked flask. After purging with nitrogen, 1.6 mL of N-methylpyrrole was added dropwise. The reaction was carried out at 80 °C for 4 h. The reaction was monitored by LC-MS until it was complete. The reaction solution was extracted with DCM and purified by column chromatography at a PE:EA ratio of 5:1 to obtain 200 mg of compound 8. The yield of the above three steps was 29.27%.

[0235] Compound 8 (200 mg), 3-methylmorpholine (200 mg), DIPEA (0.1 ml), and NMP (5 ml) were added to a 20 ml microwave tube and reacted at 150 °C for 1 h. The reaction was monitored by LC-MS until complete. PE:EA = 1:1 column purification yielded 150 mg of yellow solid compound 9, with a yield of 64.58% and m / z (ESI) = 465 (M+H). + .

[0236] Compound 9 (100 mg) was dissolved in DMSO (1.5 ml), and then 1.0 M t-BuOK / THF (2 ml) was added to the mixture. Oxygen was bubbled in while stirring for about 10 min. LC-MS monitoring showed that the reaction conversion was approximately 50%. DMSO and 1.0 M t-BuOK / THF were then added, and oxygen was bubbled in for another 10 min. LC-MS monitoring showed that the reactant concentration decreased while the product concentration increased, but some reactant remained unreacted. The product was evaporated to dryness and then transferred to liquid phase to prepare 15 mg of a yellow solid compound C-1, with a yield of 18.60%. 1 H NMR (400MHz, CDCl3) δ8.40(d,J=5.5Hz,1H),7.91(d,J=5.5Hz,1H),7.72(d,J=1.7Hz,1H),7.30(d,J =1.7Hz,1H),6.97(s,1H),6.84(dd,J=3.8,1.5Hz,1H),6.33(dd,J=3.8,2.7Hz,1H),4.82(d,J=4.2H z,1H),4.43(d,J=12.6Hz,1H),4.12(dd,J=11.2,3.3Hz,1H),4.00(s,3H),3.90(d,J=11.4Hz,1H),3 .80(dd,J=11.4,2.9Hz,1H),3.66(td,J=11.8,2.8Hz,1H),3.58–3.46(m,1H),1.46(d,J=6.8Hz,3H).

[0237] The preparation of compounds C-2, C-3, C-4, C-5, C-6, C-7, and C-8 was performed in accordance with the synthesis of compound C-1 in Example 9. The structural formulas and NMR characterization results of compounds C-2, C-3, C-4, C-5, C-6, C-7, and C-8 are shown in Table 3.

[0238] Table 3: Structural formulas and NMR characterization results of compounds C-2, C-3, C-4, C-5, C-6, C-7 and C-8

[0239]

[0240] Biological Evaluation Test Example 1: Inhibitory Effect of Compounds on ATR Enzymes The purpose of this test is to determine the inhibitory effect of IC50 on ATR enzymes. 50 The value was used to evaluate the inhibitory activity of the test compound on human ATR kinase. 1. Experimental materials:

[0241]

[0242]

[0243] 2. Test instruments

[0244] Chinese name English name model factory Kinase detector / microfluidic system Caliper EZ ReaderII Perkin Elmer

[0245] 3. Experimental Procedure

[0246] The specific experimental steps for the mobility shift assay are as follows:

[0247] All compounds were prepared to an initial concentration of 1000 / 3 times with 100% DMSO, and 40 μL was transferred to a 384-well Echo plate (Labcyte PP-0200). The compounds were also diluted with 100% DMSO, and 40 μL of 100% DMSO was transferred to two empty wells as controls without compound and enzyme. 60 nL of the compound was transferred to a 384-well reaction plate (Corning 3573) using an Echo 550. 10 μL of a 2-fold kinase solution (ATR, final concentration 5 nM) prepared with 1-fold kinase buffer (50 mM HEPES pH 7.5, 10 mM MnCl2, 1 mM DTT, and 0.0055% Brij-35) was transferred to the 384-well reaction plate, and 1-fold kinase buffer was added to the negative control wells. After mixing, incubate at room temperature for 10 minutes; add FAM-labeled peptides (final concentration 3000 nM, 5-FAM-AK-17) and ATP (final concentration 2 μM) to 1-fold kinase buffer to form a 2-fold substrate solution; transfer 10 μL of the above 2-fold substrate solution to a 384-well plate to start the reaction; incubate at 28°C for 240 minutes, and add 25 μL of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent #3 and 0.015% Brij-35) to the 384-well plate to stop the reaction.

[0248] Read the conversion rate data using CaliperEZ ReaderⅡ. Convert the conversion rate to inhibition rate data: Percentinhibition = [(MA–X) / (MA-MI)] × 100%. "MI" represents the reading of the control wells without enzyme; "MA" represents the reading of the control wells with DMSO; "X" represents the reading of different compounds in different wells. Fit the IC using XLFit excel add-in version 5.4.0.8. 50 Value. Fitting formula: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)^HillSlope)

[0249] 4. The experimental results are shown in Table 4:

[0250] Table 4: IC50 of compounds 50 value

[0251]

[0252]

[0253] In Table 4, the structure of the positive control BAY1895344 is as follows: 'a' represents IC 50 Between 10-100 nm, b represents IC. 50 Greater than 100 nM and less than or equal to 1000 nM, where c represents greater than 1000 nM.

[0254] 5. Experimental Conclusions

[0255] This experiment shows that many of the compounds in the examples have ATR enzyme activities that are superior to or comparable to the positive control BAY1895344.

[0256] Test Example 2: Experiment on the killing effect of compounds on colon cancer cells

[0257] By detecting intracellular ATP levels, based on IC50... 50 The inhibitory effects of the disclosed compounds on the proliferation of HT29 and LoVo cells were evaluated. The specific experimental methods are as follows:

[0258] 1. Experimental materials and instruments:

[0259] LoVo (human colon cancer cells), HT29 (human colon adenocarcinoma cells), fetal bovine serum (FBS) (BI, 04-002-1A), F-12K medium (Gibco, 21127-022), MoCoy's 5A medium (Gibco, 16600-082), sodium pyruvate (Invitrogen, 11360-070), DMSO (Sigma, 276855-1L), penicillin-streptomycin (Hyclone, SV30010), CellTite-Glo kit (Promega, G7571), 96-well cell culture plate (corning, 3903), 0.25% trypsin-EDTA (Invitrogen, 25200-072), XLFit software (IDBS, Version 5.5.0.5), microplate reader (EnSpire), cell counter (Vi-Cell XR).

[0260] 2. Experimental conditions:

[0261]

[0262] 3. Experimental steps:

[0263] LoVo and HT29 cells were resuscitated separately, and cell lines with good growth were selected after three passages. Cells were collected, and the cell suspension was adjusted to an appropriate concentration and added to 96-well plates at 100 μL / well. The plates were incubated overnight at 37°C with 5% CO2. The compound was added to the corresponding wells using an automated dosing system to a final concentration of 10 μM, with 3-fold dilutions, 3 replicates, and 9 concentrations compared with the 0.3% DMSO control. The plates were incubated at 37°C with 5% CO2 for 72 h. CellTiter-Glo Buffer was thawed at room temperature, and the lyophilized CellTiter-Glo substrate was equilibrated to room temperature. CellTiter-Glo Buffer was added to the CellTiter-Glo substrate and mixed thoroughly. The cell plate was removed and equilibrated to room temperature. 100 μL of the mixed CellTiter-Glo reagent was added to each well, and the plates were incubated for 30 min with shaking in the dark and for 30 min. Place the culture plate into a microplate reader, record the readings, calculate the inhibition rate, plot the drug efficacy inhibition rate curve using XLFit, and calculate the IC50. 50 value.

[0264] 4. Experimental data: Measured IC 50 The values ​​are shown in Table 5.

[0265] Table 5: IC50 of compounds in cell proliferation assay 50 value

[0266] compound <![CDATA[HT29 IC 50 (μM)]]> <![CDATA[LoVo IC 50 (μM)]]> A-3 0.852 0.141 A-6 0.305 0.045 A-7 0.331 0.081 B-2 0.705 0.165 B-3 0.103 0.016 B-11 0.319 0.043 C-3 0.218 0.024 C-4 0.321 0.056 BAY1895344 0.456 0.103

[0267] Test Example 3: Metabolic Stability Experiment of Compounds in Liver Microsomes

[0268] This experiment evaluates the metabolic stability of the test compound when incubated with liver microsomes in humans, rats, mice, dogs, and monkeys.

[0269] 1. Experimental materials and instruments:

[0270] name Supplier batch number Acetonitrile Sigma WXBD5828V DMSO Amresco 21A2756279 water Wahaha NA NADPH MCE 93125

[0271] 2. Experimental conditions:

[0272] instrument Supplier model -20℃ / 4℃ Low Temperature Refrigerator Haier BCD-269WDGB Centrifuge (6000rpm) ThermoFisher Heraeus X3R Electronic balance METTLER TOLEDO XS104 constant temperature water bath oscillator Shanghai Yiheng DK-8AX pH meter METTLER TOLEDO FE28-STANDARD Microplate oscillator IKA MTS 2 / 4 Ultra-low temperature storage box (-80℃) Thermo Fisher FDE40086FV Vortex oscillator Hangzhou Aosheng MX100-4A

[0273] 3. Experimental steps:

[0274] 3.1 Preparation of Buffer C:

[0275] Buffer A: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA);

[0276] Buffer B: 1.0 L of 0.1 M dipotassium hydrogen phosphate buffer (containing 1.0 mM EDTA);

[0277] Buffer C: Add buffer A to 700 mL of buffer B, and stop when the pH reaches 7.4.

[0278] 3.2 Preparation of 10mM stock solution:

[0279] The test compound and the reference standard were dissolved in DMSO to prepare 10 mM stock solutions.

[0280] 3.3 Preparation of the drug administration solution:

[0281] 500 μM solution: Add 10 μL of 10 mM stock solution to 190 μL of ACN;

[0282] 1.5 μM drug delivery solution (dissolved in liver microsome solution):

[0283] Add 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of buffer C, then add 1.5 μL of 500 μM solution and gently vortex to mix.

[0284] 3.4 Preparation of 6mM NADPH solution:

[0285] Weigh out NADPH and add an appropriate amount of buffer C to prepare a 6mM NADPH solution.

[0286] 3.5 Add 30 μL of 1.5 μM drug solution to wells of a 96-well plate set at different time points (0 min, 5 min, 15 min, 30 min, 45 min), with a duplication rate of 2.

[0287] 3.6 Preparation of 0-minute samples: First, add 135 μL of ACN (containing internal standard) to the well for 0 minutes, and then add 15 μL of 6 mM NADPH solution.

[0288] 3.7 Preheat the 96-well plate containing 1.5 μM drug solution and NADPH solution in a 37°C water bath for 5 minutes.

[0289] 3.8 Add 15 μL of preheated 6 mM NADPH solution to the wells set at 5 min, 15 min, 30 min, and 45 min, start the reaction and begin timing.

[0290] 3.9 When the timer displays 5 minutes, 15 minutes, 30 minutes, and 45 minutes, add 135 μL of ACN (containing internal standard) to terminate the reaction. Vortex for 10 minutes, then centrifuge the sample for 15 minutes at 5594 × g on a Thermo Multifuge × 3R centrifuge.

[0291] 3.10 Take 50 μL of supernatant from the centrifuged sample and transfer it to a 96-well plate containing 50 μL of water. Mix the samples and then send them to LC-MS / MS for analysis.

[0292] 4. Experimental data:

[0293] Note: HLM: Human liver microsomes; RLM: Rat liver microsomes; MLM: Mouse liver microsomes; DLM: Dog liver microsomes; MKLM: Monkey liver microsomes. 1 / 2 (min) represents the half-life, measured in minutes. The results are shown in the table below:

[0294]

[0295] 5. Experimental Conclusions:

[0296] Most of the compounds in the embodiments of this invention have better liver microsomal metabolic stability than the control compounds.

[0297] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0298] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

[0299] The embodiment number is only for each specific embodiment and does not lead to structural interchangeability between different embodiments.

Claims

1. A compound of the structure of Formula (Ia), (Ib) or (Ic) or a salt thereof: ， wherein, R 1 selected from the group consisting of: ; R 2 For , , , , , , , , , , , , , , , , , , , , , , , , , ; R 3 is hydrogen or C1-C4alkyl; In formula (Ib), R 2 is not .

2. The compound according to claim 1, or a salt thereof, wherein R 2 one selected from the group consisting of: 、 、 、 、 。 3. The compound according to claim 2, or a salt thereof, wherein including at least one of the following structures: (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (B-1), (B-2), (B-3), (B-5), (B-6), (B-7), (B-8), (B-9), (B-11), (B-12), (B-13), (B-14), (B-16), (B-17), (B-18), (B-19), (B-20), (B-21), (B-22), (B-23), (C-1), (C-3), (C-4), (C-5), (C-6), (C-7), (C-8).

4. A composition characterized in that, including the compound of any one of claims 1-3 or a salt thereof.

5. Use of the compound of claim 1 or a salt thereof, or the composition of claim 4 in the manufacture of a medicament for preventing or treating a hyperproliferative disease.

6. Use according to claim 5, characterized in that, The hyperproliferative disease includes psoriasis, keloid and other proliferative diseases affecting the skin, benign prostatic hyperplasia, a tumor.

7. Use according to claim 6, characterized in that, The tumor includes melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer or gallbladder cancer.

8. A combination drug composition, characterized in that, The compound of claim 1 or a salt thereof, or the composition of claim 4; and another medicament for preventing or treating a hyperproliferative disease.

9. The combination of claim 8, wherein the combination is a pharmaceutical composition. The other medicament for preventing or treating a hyperproliferative disease includes at least one of the following anticancer drugs: cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, mitoxantrone, methotrexate, methylhydroxyrosarole, etoposide, 5-azacytosine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, trastuzumab, panitumumab, inotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, denosumab, belimumab, avastin, herceptin, mabthera, imatinib, gefitinib, erlotinib, osimertinib, afatinib, icotinib, elacridar, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, taxotere, everolimus, vorinostat, romidepsin, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, zoledronic acid, bortezomib, carfilzomib, ixazomib, sonidegib, dinaciclib, thalidomide, lenalidomide, pomalidomide, venetoclax, recombinant human interleukin-2, sipueucel-T, palbociclib, olaparib, niraparib, rucaparib and talazoparib.

10. Use of the combination composition of claim 8 in the manufacture of a medicament for preventing or treating a hyperproliferative disease.

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